G-Quadruplex Identification in the Genome of Protozoan Parasites Points to Naphthalene Diimide Ligands as New Antiparasitic Agents
| العنوان: | G-Quadruplex Identification in the Genome of Protozoan Parasites Points to Naphthalene Diimide Ligands as New Antiparasitic Agents |
|---|---|
| المؤلفون: | Jose Juan Lopez-Rubio, Michela Zuffo, Juan Carlos Morales, Jean-Louis Mergny, Jenny Campos-Salinas, José M. Pérez-Victoria, Matilde Arévalo-Ruiz, Filippo Doria, Efres Belmonte-Reche, Marta Martínez-García, Mauro Freccero, Aurore Guédin, Marjorie Maynadier |
| المساهمون: | Instituto de Parasitología y Biomedicina 'López Neyra', CSIC, Imagerie Moléculaire et Nanobiotechnologies - Institut Européen de Chimie et Biologie (IECB), Université Sciences et Technologies - Bordeaux 1-Centre National de la Recherche Scientifique (CNRS), University of Pavia, Dynamique des interactions membranaires normales et pathologiques (DIMNP), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Montpellier 1 (UM1), Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud]), Institut Européen de Chimie et Biologie (IECB), Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Instituto de Investigaciones Químicas, CSIC |
| المصدر: | Journal of Medicinal Chemistry Journal of Medicinal Chemistry, American Chemical Society, 2018, 61 (3), pp.1231-1240. ⟨10.1021/acs.jmedchem.7b01672⟩ Digital.CSIC. Repositorio Institucional del CSIC instname |
| بيانات النشر: | American Chemical Society, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, Antiparasitic, medicine.drug_class, [SDV]Life Sciences [q-bio], Naphthalenes, G-quadruplex, Imides, Ligands, Genome, Cell Line, 03 medical and health sciences, chemistry.chemical_compound, Drug Discovery, parasitic diseases, medicine, Animals, Humans, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Nucleotide, Zebrafish, chemistry.chemical_classification, Regulation of gene expression, Antiparasitic Agents, Telomere, Antiparasitic agent, 3. Good health, G-Quadruplexes, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, 030104 developmental biology, Biochemistry, chemistry, Kinetoplast, Molecular Medicine, Genome, Protozoan, DNA |
| الوصف: | G-quadruplexes (G4) are DNA secondary structures that take part in the regulation of gene expression. Putative G4 forming sequences (PQS) have been reported in mammals, yeast, bacteria, and viruses. Here, we present PQS searches on the genomes of T. brucei, L. major, and P. falciparum. We found telomeric sequences and new PQS motifs. Biophysical experiments showed that EBR1, a 29 nucleotide long highly repeated PQS in T. brucei, forms a stable G4 structure. G4 ligands based on carbohydrate conjugated naphthalene diimides (carb-NDIs) that bind G4's including hTel could bind EBR1 with selectivity versus dsDNA. These ligands showed important antiparasitic activity. IC50 values were in the nanomolar range against T. brucei with high selectivity against MRC-5 human cells. Confocal microscopy confirmed these ligands localize in the nucleus and kinetoplast of T. brucei suggesting they can reach their potential G4 targets. Cytotoxicity and zebrafish toxicity studies revealed sugar conjugation reduces intrinsic toxicity of NDIs. This work was supported by the Spanish Ministerio de Economía y Competitividad (Grants CTQ2012-35360, CTQ2015-64275-P, and SAF2016-80228-R), Junta de Andalucía (Grant BIO1786), Worldwide Cancer Research Foundation (Grant 16-0290), Italian Association for Cancer Research (AIRC, Grant IG2013-14708), Agence Nationale de la Recherche (ANR Quarpdiem, Grant ANR-12-BSV8-0008-01), the SYMBIT project (Reg. No. CZ.02.1.01/0.0/0.0/15_003/0000477) financed by the ERDF, and FEDER funds from the EU are gratefully acknowledged. M.A.-R. and M.M.-G. thank Ministerio de Educación, Cultura y Deporte for a FPU and a FPI predoctoral fellowship, respectively. E.B.-R. is a student of the pharmacy Ph.D. program of the University of Granada (Spain). |
| اللغة: | English |
| تدمد: | 0022-2623 1520-4804 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9b37134663c264709b225f4f349119ae http://hdl.handle.net/10261/163518 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....9b37134663c264709b225f4f349119ae |
| قاعدة البيانات: | OpenAIRE |
Find this issue from the American Chemical Society | تدمد: | 00222623 15204804 |
|---|